Lineage switch from acute myeloid leukemia to B‐lymphoblastic lymphoma with an acquired <scp><i>PIK3R1</i></scp> loss‐of‐function mutation
Authors: Monica Aldulescu, Katrin Leuer, Lawrence J. Jennings, Kai Lee Yap, Shunyou Gong
Journal: American Journal of Hematology (2022)

"Lineage switch" is a term used to describe the phenomenon of acute leukemias that meet standard criteria for a specific lineage (either lymphoid or myeloid) at the time of initial diagnosis, but later switch to another lineage upon relapse.1 Most reports of lineage switching have occurred in children and demonstrated acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) conversion. Cases of lineage switch vice versa were only rarely reported. Moreover, the molecular mechanisms underlying lineage switch in either direction remain poorly understood. Herein, we report a case of lineage switch occurring in a 2-year-old girl with acquired loss-of-function mutation of PIK3R1, potentially responsible for the myeloid to lymphoid switch of her malignant cells. The patient originally presented at 8 months of age with vomiting and diarrhea. She was found to have leukocytosis (WBC 110.9 × 103/μl), anemia (Hemoglobin 8.2 g/dl), and thrombocytopenia (platelets 62 × 103/μl). WBC differential count revealed 47% blasts. The blasts on bone marrow aspirate were large, with pale cytoplasm containing finely dusty granules, oval nuclei, dispersed chromatin, and prominent nucleoli (Figure 1). By cytochemical stains, the blasts were negative for myeloperoxidase (MPO), and positive for non-specific esterase (NSE), whose activity was completely inhibited by NaF, suggestive of monocytic lineage. By flow cytometry, the blasts were positive for CD45 (dim), CD117 (partial), CD33, CD38, HLA-DR, and CD4, mostly negative for CD13 (5.3% positive), negative for CD34, CD14, CD15, CD36, TdT, CD19, CD79a, CD22, CD24, CD58, CD20, CD10, CD3, CD2, CD5, CD7, CD8, CD25, and CD56 (Figure 1). The patient was diagnosed with acute myeloid leukemia (AML-M5). Chromosome studies revealed 46,XX,t(9;11)(p22;q23). Interphase FISH was positive for KMT2A (MLL) rearrangement (Figure 1). Oncokids, a widely used next-generation (NGS) sequencing panel for pediatric malignancies,2 identified MLL-AF9 gene fusion. She received chemotherapy per COG AAML1031, a routine chemotherapy regimen for pediatric low-risk AML, and achieved complete remission. However, 14 months after completion of AML therapy she presented with a 2.5 cm right frontoparietal scalp mass which was suspected to be myeloid sarcoma, and then biopsied for definitive diagnosis. Histologic sections of the scalp mass revealed a dense dermal infiltrate with bottom-heavy pattern and largely sparing superficial dermis. The infiltrate is composed of medium-sized atypical cells with oval nuclei, dispersed chromatin, and small nucleoli, with scattered small mature lymphocytes in the background (Figure 1). By immunohistochemistry and flow cytometry, the tumor cells in the scalp mass were positive for CD45 (dim), HLA-DR, CD19, CD79a, CD22, CD24, CD38, CD58, with a spectrum of CD20, negative for CD34, TdT, CD10, kappa, lambda, CD138, myeloperoxidase, lysozyme, CD13, CD33, CD3, CD2, CD5, CD7, CD4, CD8, CD21, CD25, CD56, and EBER (Figure 1). Ki-67 labeled approximately 80% of the tumor cells. This lesion was diagnosed as B-lymphoblastic lymphoma (B-LBL). Chromosome study failed due to insufficient cells harvested from the tissue. However, interphase FISH was positive for KMT2A (MLL) rearrangement (Figure 1). NGS panel revealed MLL-AF9 gene fusion and PIK3R1 splice site 1300-1_1300GG > AA, a variant of potential clinical significance which was confirmed by Sanger sequencing. Cutaneous B-LBL is a rare lymphoid neoplasm that occurs more frequently in children. To the best of our knowledge, the development of cutaneous B-LBL from pre-existing AML has not been described, although there were a few B-lymphoblastic leukemia cases reportedly transformed from AML in the literature. In our case, the identical KMT2A (MLL)-AF9 gene fusion was found in the scalp B-LBL as well as the AML diagnosed 18 months earlier, confirming clonal relationship of the two neoplasms. KMT2A (MLL) rearrangements have been described in acute myeloid and lymphoblastic leukemias and confer a worse prognosis. Many cases of acute leukemia with lineage switch involved KMT2A (MLL) gene although the mechanisms underlying the switch are not well understood. Currently, a few models have been proposed to explain this phenomenon. The first theory is that the original leukemic clone, although committed to a specific lineage at initial diagnosis, keeps some degrees of lineage plasticity (stem cell plasticity model), and it may undergo alteration of cell phenotype through reactivation of a stem cell program.3 The second proposal suggests that tumors retain oligopotential progenitors (common progenitor model), which were induced to differentiate to another lineage by intracellular events or extracellular environments. The roles of tumor microenvironment in lineage switch have been experimentally proven in mouse models.4 The last hypothesis is the clonal selection model, which argues that the original tumor may be heterogeneous and contain a few blasts of another lineage, that eventually outgrow after chemotherapy killed the dominant clone.5 No core biopsy or clot was obtained at the time of initial AML diagnosis for our patient, precluding additional immunohistochemical stains of B-cell markers in the original specimen. However, we re-analyzed the flow cytometry plots and found no expression of B-cell and/or lymphoblastic markers (CD19, CD20, CD79a, CD22, TdT) by the blast population, making the clonal selection model unlikely. The stem cell plasticity or common progenitor models may better explain our case. The scalp B-LBL and previous AML shared the same driver genetic changes KMT2A (MLL)-AF9. However, the PIK3R1 mutation was found in the scalp B-LBL but not in the original AML, suggestin that it was a novel genetic alteration acquired after the initial diagnosis, likely secondary to chemotherapy. Although we do not have supporting experimental evidence, this PIK3R1 mutation may be a genetic event that contributed to the lineage switch. PIK3R1 encodes the p85-alpha regulatory subunit of phosphatidylinositol 3- kinase (PI3K). Splicing site mutation leads to a truncated protein with inactivated kinase function. PIK3R1 mutations have been linked to the pathogenesis of several neoplasms including Burkitt lymphoma.6 In summary, this case represents the first report of lineage switch from AML to B-LBL involving the skin. The original AML clone, or the common progenitor among the first tumor, may have trans-differentiated to the new B-LBL with underlying genetic changes at least partially attributable to this PIK3R1 mutation. Knocking down of PIK3R1 gene expression in AML cell line may help elucidate whether loss of function of this gene plays a role in myeloid to lymphoid lineage switch. There is no conflict of interest to declare. The data that supported the findings of this study are available on request from the corresponding author.